Loss of the collagen IV modifier prolyl 3-hydroxylase 2 causes thin basement membrane nephropathy

Aypek H, Krisp C, Lu S, Liu S, Kylies D, Kretz O, Wu G, Moritz M, Amann KU, Benz K, Tong P, Hu ZM, Alsulaiman SM, Khan AO, Grohmann M, Wagner T, Müller-Deile J, Schlüter H, Puelles VG, Bergmann C, Huber TB, Grahammer F (2022)

Publication Type: Journal article

Publication year: 2022

Journal

Journal of Clinical Investigation American Society for Clinical Investigation

Book Volume: 132

Article Number: e147253

Journal Issue: 9

DOI: 10.1172/JCI147253

Abstract

The glomerular filtration barrier (GFB) produces primary urine and is composed of a fenestrated endothelium, a glomerular basement membrane (GBM), podocytes, and a slit diaphragm. Impairment of the GFB leads to albuminuria and microhematuria. The GBM is generated via secreted proteins from both endothelial cells and podocytes and is supposed to majorly contribute to filtration selectivity. While genetic mutations or variations of GBM components have been recently proposed to be a common cause of glomerular diseases, pathways modifying and stabilizing the GBM remain incompletely understood. Here, we identified prolyl 3-hydroxylase 2 (P3H2) as a regulator of the GBM in an a cohort of patients with albuminuria. P3H2 hydroxylates the 3′ of prolines in collagen IV subchains in the endoplasmic reticulum. Characterization of a P3h2ΔPod mouse line revealed that the absence of P3H2 protein in podocytes induced a thin basement membrane nephropathy (TBMN) phenotype with a thinner GBM than that in WT mice and the development of microhematuria and microalbuminuria over time. Mechanistically, differential quantitative proteomics of the GBM identified a significant decrease in the abundance of collagen IV subchains and their interaction partners in P3h2ΔPod mice. To our knowledge, P3H2 protein is the first identified GBM modifier, and loss or mutation of P3H2 causes TBMN and focal segmental glomerulosclerosis in mice and humans.

Authors with CRIS profile

Kerstin Ute Amann Professur für Nephropathologie Kerstin Benz Medizinische Fakultät Janina Müller-Deile Department of Medicine 4 – Nephrology and Hypertension

Involved external institutions

Central South University CN China (CN) Medizinische Genetik Mainz DE Germany (DE) Universitätsklinikum Hamburg-Eppendorf (UKE) DE Germany (DE) Cleveland Clinic Abu Dhabi LLC AE United Arab Emirates (AE) King Khaled Eye Specialist Hospital SA Saudi Arabia (SA)

How to cite

APA:

Aypek, H., Krisp, C., Lu, S., Liu, S., Kylies, D., Kretz, O.,... Grahammer, F. (2022). Loss of the collagen IV modifier prolyl 3-hydroxylase 2 causes thin basement membrane nephropathy. Journal of Clinical Investigation, 132(9). https://doi.org/10.1172/JCI147253

MLA:

Aypek, Hande, et al. "Loss of the collagen IV modifier prolyl 3-hydroxylase 2 causes thin basement membrane nephropathy." Journal of Clinical Investigation 132.9 (2022).

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